High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations

Heesterman, Berdine L.; Bayley, Jean Pierre; Tops, Carli M.J.; Hes, Frederik J.; Brussel, Bernadette T J van; Corssmit, Eleonora P M; Hamming, Jaap F.; Mey, Andel G. L. van der; Jansen, Jeroen C.

doi:10.1038/ejhg.2012.203

Cited by 36 publications

(41 citation statements)

References 10 publications

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“…One retrospective study that corrected for ascertainment bias and missing pedigree information estimated that the penetrance of SDHB mutation was 21% by age 50 years and 42% by age 70 years similar to a large study with 673 SDHB carriers that estimated penetrance to be 22–24% by 60 years and 30.6% by age 80 years . Surveillance studies using magnetic resonance imaging (MRI) have shown that 12–18% of asymptomatic SDHB carriers developed PPGL within 4–9 years, further supporting lower penetrance .…”

Section: Clinical Characteristics (See Table For a Summary)mentioning

confidence: 99%

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Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

et al. 2019

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Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first‐degree relatives (and second‐degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy‐catecholamines and bi‐annual rapid whole‐body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre‐symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow‐up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

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Section: Clinical Characteristics (See Table For a Summary)mentioning

confidence: 99%

“…showed that 59% of 41 asymptomatic SDHD carriers had a head and neck PGL upon screening with MRI. In addition, six carriers developed symptoms suggestive of a PGL that could later be detected with MRI .…”

Section: Clinical Characteristics (See Table For a Summary)mentioning

confidence: 99%

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

et al. 2019

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“…PGL paraganglioma, PCC, phaeochromocytoma, Abdo PGL abdominal paraganglioma, HNPGL head & neck paraganglioma. * Based on studies including: Astuti 2003, Neumann 2004, Benn 2006, Timmers 2007, Solis 2009, King 2011, Ayala‐Raimez 2011, Rijken 2016, Jasperson 2014, Papathomas 2015, Daniel 2016, Eijkelenkamp 2014, Tufton 2016, Niemeijer 2017; **Astuti 2001, Cascon 2002, Neumann 2002, Neumann 2004, Astuti 2003, Dannenberg 2005, Simi 2005, Benn 2006, Fish 2007, Havekes, 2007, Timmers 2008, Mannelli 2009, Neumann 2009, Heesterman 2013, Miederer 2013, Papathomas 2015, Daniel 2016 [Colour figure can be viewed at wileyonlinelibrary.com]…”

Section: Surveillance Programmesmentioning

confidence: 99%

Can subunit‐specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?

Tufton

Sahdev

Drake

et al. 2018

Clinical Endocrinology

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Objective: With the discovery that familial phaeochromocytoma and paraganglioma syndrome can be caused by mutations in each subunit of the succinate dehydrogenase enzyme (SDH), has come the recognition that mutations in the individual subunits have their own distinct natural histories. Increased genetic screening is leading to the identification of increasing numbers of, mostly asymptomatic, gene mutation carriers and the implementation of screening strategies for these individuals. Yet there is, to date, no international consensus regarding screening strategies for asymptomatic carriers.Design: A comprehensive PubMed search from 1/1/2000 to 28/2/2018 was undertaken using multiple search terms and subsequently a manual review of references in identified papers to identify all clinically relevant cases and cohorts. In this review, the accumulated, published experience of phenotype and malignancy risks of individual SDH subunits is analysed. Where possible screening results for asymptomatic SDH mutation carriers have been analysed separately to define the penetrance in asymptomatic carriers (asymptomatic penetrance). Results:The combined data confirms that "asymptomatic penetrance" is highest for SDHD and when there is penetrance, the most likely site to develop a PGL is head and neck (SDHD) and extra-adrenal abdominal (SDHB). However, the risk in SDHB carriers of developing HNPGL is also high (35.5%) and a PCC is low (15.1%), and in SDHD carriers there is a high risk of developing a PCC (35.8%) or abdominal PGL (9.4%) and a small, but significant risk at other sympathetic sites. The data suggest that the risk of malignant transformation is the same for both PCC and extra-adrenal abdominal PGLs (30%-35%) in SDHB carriers. In SDHD carriers, the risk of malignant transformation was highest in HNPGLs (7.5%) and similar for sympathetic sites (3.8%-5.2%). Conclusions:Using this data, we suggest surveillance screening of asymptomatic carriers can be tailored to the underlying SDH subunit and review possible surveillance programmes. K E Y W O R D S imaging, MRI, paraganglioma, phaeochromocytoma, screening, SDH, succinate dehydrogenase, surveillance S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Tufton N, Sahdev A, Drake WM, Akker SA. Can subunit-specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?. Clin Endocrinol. 2019;90:31-46. https://doi.

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“…43,98 However, they can cause significant morbidity by virtue of their proximity to critical neural and vascular structures in the brain and neck, including the carotid artery, jugular vein, and cranial nerves (CNs) VII-XII. In this regard, the most common presenting symptoms include pain, dysphagia, hoarseness, pulsatile tinnitus, and conductive hearing loss.…”

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confidence: 99%

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

Hussain¹,

Husain²,

Baredes

et al. 2014

JNS

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Paragangliomas are rare neuroendocrine tumors derived from neural crest cells of the autonomic nervous system. Tumors occurring in the thorax, abdomen, and pelvis are usually derived from sympathetic paraganglia, which are associated with catecholaminemia, headaches, and resistant hypertension. Pheochromocytomas, arising from chromaffin cells of the adrenal medulla, are histologically similar to sympathetic paragangliomas and can have identical clinical presentations. In contrast to these tumors, skull base and head and neck region paragangliomas (SHN-PGs) are usually derived from parasympathetic paraganglia and rarely secrete catecholamines. These tumors can present in a variety of locations, most commonly arising from glomus Type I (chief) cells of the carotid body. Less commonly they arise in regions of the temporal bone including the middle ear (glomus tympanicum) and jugular fossa (glomus jugulare) (Fig. 1A), as well as along the length of the vagus nerve (glomus vagale) and in the nose and paranasal sinuses (sinonasal paraganglioma). 60,69,75,77,93,99 These tumors Paragangliomas are rare, slow-growing tumors that frequently arise in the head and neck, with the carotid bodies and temporal bone of the skull base being the most common sites. These neoplasms are histologically similar to pheochromocytomas that form in the adrenal medulla and are divided into sympathetic and parasympathetic subtypes based on functionality. Skull base and head and neck region paragangliomas (SHN-PGs) are almost always derived from parasympathetic tissue and rarely secrete catecholamines. However, they can cause significant morbidity by mass effect on various cranial nerves and major blood vessels. While surgery for SHN-PG can be curative, postoperative deficits and recurrences make these lesions challenging to manage. Multiple familial syndromes predisposing individuals to development of paragangliomas have been identified, all involving mutations in the succinate dehydrogenase complex of mitochondria. Mutations in this enzyme lead to a state of "pseudohypoxia" that upregulates various angiogenic, survival, and proliferation factors. Moreover, familial paraganglioma syndromes are among the rare inherited diseases in which genomic imprinting occurs. Recent advances in gene arrays and transcriptome/exome sequencing have identified an alternate mutation in sporadic SHN-PG, which regulates proto-oncogenic pathways independent of pseudohypoxia-induced factors. Collectively these findings demonstrate that paragangliomas of the skull base and head and neck region have a distinct genetic signature from sympathetic-based paragangliomas occurring below the neck, such as pheochromocytomas. Paragangliomas serve as a unique model of primarily surgically treated neoplasms whose future will be altered by the elucidation of their genomic complexities. In this review, the authors present an analysis of the molecular genetics of SHN-PG and provide future directions in patient care and the development of novel therapies. 321Abbreviations used in ...

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High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations

Cited by 36 publications

References 10 publications

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

Can subunit‐specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

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